The present invention relates to a method for reductive elimination of a protecting group from an amino acid or a peptide as well as a derivative thereof such as esters or amides having at least one functional group protected by the protecting group.
It is well known in the art that, in the course of synthetic preparation of many kinds of amino acids or peptides, the final stage of the process may be the reductive elimination of a protecting group from a protected amino acid or peptide having at least one functional group protected by the protecting group so as that the protected amino acid or peptide is converted into the desired product. It is usual in the prior art that the reaction of the above reductive elimination of the protecting proups is carried out in a solution with an organic solvent capable of dissolving both the protected starting material and the freed amino acid, peptide or derivative thereof in the presence of a catalyst for hydrogen reduction as dipersed therein. A problem in this procedure is that, owing to the solubility behavior of the starting material and the product in the solvent, it is sometimes difficult to obtain clear separation of the product from the unreacted starting material or from the catalyst.
On the other hand, it has been proposed to use such a solvent as the reaction medium that the starting material can be dissolved but the product compound is hardly soluble therein. In this case, the reaction mixture exhibits a slurry-like or gel-like consistency at a stage where the desired reaction has proceeded to some extent and the completeness of the reaction cannot be expected presenting a great practical drawback even by setting aside the disadvantage of troublesome handling of such a slurry-like or gel-like reaction mixture of high consistency.
The above situation is specifically explained for the preparation of a lower alkyl, e.g. methyl, ester of .alpha.-L-aspartyl-L-phenylalanine as a typical example. The above compound is a promising artificial sweetening agent and it has been eagerly desired to develop an efficient and economical method for the synthetic preparation thereof. The synthetic preparation of the compound is most conveniently performed by the route of an N-benzyloxycarbonyl-substituted compound as an intermediate and the final stage of the process is the elimination of the benzyloxycarbonyl group from the substituted intermediate compound by the catalytic reduction with hydrogen to liberate the desired compound. This reductive elimination reaction of the benzyloxycarbonyl group is usually carried out in a mixed solvent of water and methyl alcohol but one of the problems involved in this process is, in addition to the above described disadvangates in the reductive elimination of the protecting groups in general, that a diketopiperazine is unavoidably produced leading to a great decrease in the yield of the desired compound.